Imidazolinone derivatives as tachykinin receptor antagonists

ABSTRACT

Compounds of formula (I) and salts and prodrugs wherein Q 1  is a specified aryl group, the dotted line is an optional double bond, Z is O or NR 3 , R 1  and R 3  are H or specified optionally substituted alkyl or other substituents and R 2  is an optionally substituted phenyl or group are tachykinin receptor antagonists useful in medicine.

This application is a 371 of PCT/GB93/02131, filed Oct. 14, 1993.

This invention relates to a class of heterocyclic compounds, inparticular imidazolinone and oxazolinone derivatives, which are usefulas tachykinin receptor antagonists.

The tachykinins are a group of naturally-occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in the peripheral nervous and circulatory systems.The three known mammalian tachykinins are: substance P, neurokinin A andneurokinin B:

Evidence for the usefulness of tachykinin receptor antagonists in pain,headache, especially migraine, Alzheimer's disease, multiple sclerosis,attenuation of morphine withdrawal, cardivascular changes, oedema, suchas oedema caused by thermal injury, chronic inflammatory diseases suchas rheumatoid arthritis, asthma/bronchial hyperreactivity and otherrespiratory diseases including allergic rhinitus, inflammatory diseasesof the gut including ulcerative colitis and Crohn disease, ocular injuryand ocular inflammatory diseases, proliferative vitreoretinopathy,irritable bowel syndrome and disorders of bladder function includingcystitis and bladder detruser hyperreflexia is reviewed in "TachykininReceptors and Tachykinin Receptor Antagonists", C. A. Maggi, RPatacchini, P. Rovero and A. Giachetti, J. Auton. Pharmacol. (1993) 13,23-93. Tachykinin antagonists are also believed to be useful in allergicconditions [Hamelet et al Can. J. Pharmacol. Physiol. (1988) 66 1361-7],immunoregulation [Lotz et al Science (1988) 241 1218-21 and Kimball etal, J. Immunol. (1988) 141 (10) 3564-9], and as anticonvulsants [Garantet al., Brain Research (1986) 382 372-8]. Tachykinin antagonists mayalso be useful in the treatment of small cell carcinomas, in particularsmall cell lung cancer (SCLC) [Langdon et al., Cancer Research (1992)52, 4554-7].

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophillicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosis (Europeanpatent application no. 0 436 334), conjuctivitis, vernal conjunctivitis,contact dermatitis, atropic dermatitis, urticaria, and other eczematoiddermatitis (European patent application no. 0 394 989) and emesis(European patent application no. 0 533 280).

We have now found a class of non-peptides which are potent antagonistsof tachykinins.

The present invention provides a compound of formula (I), or a salt orprodrug thereof: ##STR2## wherein

Q¹ represents a phenyl group substituted by one or more halo, optionallysubstituted naphthyl, optionally substituted indolyl, optionallysubstituted benzthiophenyl, optionally substituted benzofuranyl,optionally substituted benzyl or optionally substituted fluorenyl;

the dotted line represents an optional covalent bond;

one of A¹ and A² represents NR¹ and the other is Z where Z represents Oor NR³ ;

R¹ and R³ each independently represent H; C₁₋₆ alkyl optionallysubstituted by hydroxy, cyano, COR^(c), CO₂ R^(c), CONR^(c) R^(d), orNR^(c) R^(d) (where R^(c) and R^(d) each independently represent H, C₁₋₆alkyl or C₀₋₄ alkylphenyl optionally substituted in the phenyl ring byone or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo or trifluoromethylmethyl);phenyl(C₁₋₄ alkyl) (optionally substituted in the phenyl ring by one ormore of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo and trifluoromethyl); COR^(c) ;CO₂ R^(c) ; CONR^(c) R^(d) ; COC₁₋₄ alkylNR^(c) R^(d) ; CONR^(c)COOR^(d) ; SO₂ R^(c), where R^(c) and R^(d) are as above defined; WR⁶ orCO--Y--W--R⁶ where R⁶ is an optionally substituted aromatic ornon-aromatic azacyclic or azabicyclic group, Y is a bond, O, S orNR^(y), where R^(y) is H or C₁₋₆ alkyl, and W represents a bond or asaturated or unsaturated hydrocarbon chain of 1, 2, 3, 4, 5 or 6 carbonatoms;

R² represents phenyl optionally substituted by 1, 2, or 3 groupsselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano,nitro, trifluoromethyl, trimethylsilyl, OR^(a), SR^(a), SOR^(a), NR^(a)R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b), CO₂ R^(a) or CONR^(a) R^(b),where R^(a) and R^(b) independently represent H, C₁₋₆ alkyl, phenyl ortrifluoromethyl.

For the avoidance of doubt, when the covalent bond represented by thedotted line is present, the compounds of formula (I) contain an olefinicdouble bond.

Aptly, this invention provides a compound of the formula (I) or apharmaceutically acceptable salt thereof.

As used herein, the definition of each expression, when it occurs morethan once in any structure, is intended to be independent of itsdefinition elsewhere in the same structure.

The alkyl, alkenyl and alkynyl groups referred to with respect to any ofthe above formulae may represent straight, branched or cyclic groups orcombinations thereof. Thus, for example, suitable alkyl groups includemethyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cycloalkyl-alkylgroups such as cyclopropylmethyl; suitable alkenyl groups include vinyland allyl; and suitable alkynyl groups include propargyl.

The term "halo" as used herein includes fluoro, chloro, bromo and iodo,especially chloro and fluoro.

Where Q¹ represents optionally substituted fluorenyl, the group islinked through the bridgehead carbon atom, that is to say, C-9.

Where Q¹ represents optionally substituted naphthyl, indolyl,benzothiophenyl, benzofuranyl, benzyl or fluorenyl, suitablesubstituents include C₁₋₆ alkyl, C₁₋₆ alkenyl, C₂₋₆ alkynyl, halo,cyano, nitro, trifluoromethyl, trimethylsilyl, SR^(a), SOR^(a), SO₂R^(a), OR^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) COOR^(b), COOR^(a)or CONR^(a) R^(b), where R^(a) and R^(b) are as above defined. One ormore substituents may be present and each may be located at anyavailable ring position, except, where Q¹ is optionally substitutedindolyl, the nitrogen atom. Where Q¹ is optionally substituted indolyl,suitable nitrogen substituents include C₁₋₆ alkyl, optionallysubstituted phenyl(C₁₋₄ alkyl), COOR^(a) or CONR^(a) R^(b), whereinR^(a) and R^(b) are as above defined.

Suitable values of the group Q¹ include 3,4-dichlorophenyl, 3-indolyl,2-naphthyl, 3-naphthyl, 9-fluorenyl, benzyl, 3-benzothiophenyl and3-benzofuranyl.

Preferably Q¹ is 3-indolyl, 3-benzothiophenyl or 3,4-dichlorophenyl,more preferably 3-indolyl.

The aromatic or non-aromatic azacycle or azabicycle R⁶ may contain oneor more additional heteroatoms selected from O and S, or groups NR⁷,where R⁷ is H or C₁₋₆ alkyl, and may be unsubstituted or substituted.Suitable substituents include C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, SH, ═S,halo, trifluoromethyl, NR^(a) R^(b), NR^(a) COR^(b), CONR^(a) R^(b), CO₂R^(a) and CH₂ OR^(a), where R^(a) and R^(b) are as previously defined.

When R⁶ represents an aromatic azacycle or azabicycle, suitable valuesof R⁶ include imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl,pyrrolyl, pyrazolyl, pyrazinyl, pyridyl, oxadiazolyl, thiadiazolyl,isoxazolyl, isothiazolyl, benzimidazolyl, benzoxazolyl and indolyl,preferably imidazolyl, such as 2,4-imidazolyl, or pyridyl such as 4-, 3-or 2-pyridyl.

When R⁶ represents a non-aromatic azacycle or azabicycle, suitablevalues of R⁶ include morpholinyl, piperdinyl, pyrrolidinyl, piperazinyl,methylpiperazinyl, azanorbornanyl, 3,4-pyridinecarboxamido,quinuclidinyl, and azabicyclo[3.2.2]nonyl, preferably morpholinyl,piperazinyl, methylpiperazinyl, piperidinyl, pyrrolidinyl, quinuclidinyl(azabicyclo[2.2.2]octanyl) or azabicyclo[3.2.2]nonyl.

A subgroup of compounds according to the invention is represented bycompounds of formula (I) wherein R¹ and R³ each independently representH; C₁₋₆ alkyl optionally substituted by hydroxy, cyano, COR^(c), CO₂R^(c), CONR^(c) R^(d), or NR^(c) R^(d) (where R^(c) and R^(d) are aspreviously defined); phenyl(C₁₋₄ alkyl) (optionally substituted in thephenyl ring by one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo andtrifluoromethyl); COR^(c) ; CO₂ R^(c) ; CONR^(c) R^(d) ; COC₁₋₄alkylNR^(c) R^(d) ; CONR^(c) COOR^(d) ; SO₂ R^(c) ; (CH₂)_(q) R⁶ orCO(CH₂)_(q) R⁶ where R⁶ is as previously defined and q is 0, 1, 2, 3, 4,5 or 6.

Preferably the double bond is present.

Aptly, A¹ represents O. In one group of particularly apt compounds A¹ isNR¹.

Preferably Z is NR³.

In one group of compounds according to the invention, R³ is preferably Hor C₁₋₃ alkyl, such as methyl.

In a preferred group of compounds of formula (I), R³ represents C₁₋₆alkyl substituted by NR^(c) R^(d) where R^(c) and R^(d) preferablyrepresent C₁₋₆ alkyl, such as C₁₋₄ alkyl, e.g. methyl, or Y--W--R⁶,where Y preferably represents a bond, W preferably represents a bond orC₁₋₄ alkyl and R⁶ is preferably pyridyl, especially 4-pyridyl,pyridinyl, such as 4-pyridinyl, or morpholinyl.

Preferably R¹ is H.

Preferably R² represents substituted phenyl. Suitable phenylsubstituents include nitro, trifluoromethyl, trimethylsilyl, bromo,chloro, fluoro, iodo, cyano, methyl, ethyl, cyclopropyl, vinyl, methoxy,phenoxy and amino. Preferably R² represents monosubstituted or, morepreferably, disubstituted phenyl wherein the substituents are selectedfrom C₁₋₆ alkyl, such as methyl, ethyl or t-butyl, C₁₋₆ alkoxy, such asmethoxy, halo such as bromo, chloro, fluoro or iodo, andtrifluoromethyl. When R² represents monosubstituted phenyl, thesubstituent is preferably in the 3-position. When R² representsdisubstituted phenyl, the substituents are preferably in the 3- and5-positions.

Particularly preferred are compounds wherein R² represents3,5-bis(trifluoromethyl)phenyl.

A particular subgroup of compounds according to the invention isrepresented by compounds of formula (Ia), and salts and prodrugsthereof: ##STR3## wherein the dotted line represents an optionalcovalent bond;

X represents O, S or NR¹⁴ (where R¹⁴ is H, C₁₋₆ alkyl, optionallysubstituted phenyl(C₁₋₄ alkyl), CO₂ R^(a) or CONR^(a) R^(b), where R^(a)and R^(b) are as previously defined), preferably S or NH;

Z is as defined for formula (I);

R¹ is as defined for formula (I), preferably H;

R¹¹ and R¹² each independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl,OR^(a), SR^(a), SOR^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b),CO₂ R^(a) or CONR^(a) R^(b), where R^(a) and R^(b) are as previouslydefined;

each R¹³ may occupy any available carbon atom of the bicyclic ringsystem and independently represents C₁₋₆ alkyl, C₂₋ alkenyl, C₂₋alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR^(a),SR^(a), SOR^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b), CO₂R^(a) or CONR^(a) R^(b), where R^(a) and R^(b) are as previouslydefined; and

n is 0, 1, 2 or 3, preferably 0.

Preferred are compounds of formula (Ia) wherein the optional covalentbond is present.

A further subgroup of compounds according to this invention areanalogues of the compounds of the formula (Ia) but wherein NR¹ isreplaced by O and Z is NR³.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable non-toxic acid such as hydrochloric acid,sulphuric acid, oxalic acid, fumaric acid, p-toluenesulphonic acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Salts of amine groups may alsocomprise quaternary ammonium salts in which the amino nitrogen atomcarries a suitable organic group such as an alkyl, alkenyl, alkynyl oraralkyl moiety. Furthermore, where the compounds of the invention carryan acidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude metal salts such as alkali metal salts, e.g. sodium or potassiumsalts; and alkaline earth metal salts, e.g. calcium or magnesium salts.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

The compounds according to the invention may exist both as enantiomersand as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The substance P antagonising activity of the compounds described hereinwas evaluated using the human NK1R assay described in published Europeanpatent application no. 0 528 495. The method essentially involvesdetermining the concentration of the test compound required to reduce by50% the amount of radiolabelled substance P binding to human NK1R,thereby affording an IC₅₀ value for the test compound. The compounds ofthe Examples were found to have IC₅₀ values of less than 500 nM.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, solutions or suspensions, or suppositories, for oral,parenteral or rectal administration, or topical administration includingadministration by inhalation or insufflation.

The invention further provides a process for the preparation of apharmaceutical composition comprising a compound of formula (I), or asalt or prodrug thereof, and a pharmaceutically acceptable carrier,which process comprises bringing a compound of formula (I), or a salt orprodrug thereof into association with a pharmaceutically acceptablecarrier.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are adminsitered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

For topical administration, for example as a cream, ointment or lotion,pharmaceutically acceptable carriers are, for example, water, mixturesof water and water-miscible solvents such as lower alkanols orarylalkanols, vegetable oils, polyalkylene glycols, petroleum basedjelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose,polyvinylpyrrolidone, isopropyl myristate and otherconventionally-employed non-toxic, pharmaceutically acceptable organicand inorganic carriers. The pharmaceutical preparation may also containnon-toxic auxiliary substances such as emulsifying, preserving, wettingagents, bodying agents and the like, as for example, polyethyleneglycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and10,000, antibacterial components such as quaternary ammonium compounds,phenylmercuric salts known to have cold sterilizing properties and whichare non-injurious in use, thimerosal, methyl and propyl paraben, benzylalcohol, phenyl ethanol, buffering ingredients such as sodium chloride,sodium borate, sodium acetates, gluconate buffers, and otherconventional ingredients such as sorbitan monolaurate, triethanolamine,oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodiumsulfosuccinate, monothioglycerol, thiosorbitol, ethylenediaminetetraacetic acid, and the like.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity. Thesemay include disorders of the central nervous system such as anxiety,depression, psychosis and schizophrenia; epilepsy; neurodegenerativedisorders such as dementia, including senile dementia of the Alzheimertype, Alzheimer's disease and Down's syndrome; demyelinating diseasessuch as multiple sclerosis (MS) and amyotropic lateral sclerosis (ALS;Lou Gehrig's disease) and other neuropathological disorders such asperipheral neuropathy, for example, diabetic or chemotherapy-inducedneuropathy, and postherpetic and other neuralgias; small cell carcinomasuch as small cell lung cancer; respiratory diseases such as chronicobstructive airways disease, bronchopneumonia, bronchospasm and asthma;inflammatory diseases such as inflammatory bowel disease, irritablebowel syndrome, psoriasis, fibrositis, osteoarthritis and rheumatoidarthritis; allergies such as eczema and rhinitis; hypersensitivitydisorders such as poison ivy; ophthalmic diseases such asconjunctivitis, vernal conjunctivitis, and the like, and proliferativevitreoretinopathy; cutaneous diseases such as contact dermatitis,atropic dermatitis, urticaria, and other eczematoid dermatitis; oedema,such as oedema caused by thermal injury; addiction disorders such asalcoholism; stress related somatic disorders; reflex sympatheticdystrophy such as shoulder/hand syndrome; dysthymic disorders; adverseimmunological reactions such as rejection of transplanted tissues anddisorders related to immune enhancement or suppression such as systemiclupus erythematosis; gastrointestinal (GI) disorders and diseases of theGI tract such as disorders associated with the neuronal control ofviscera such as ulcerative colitis, Crohn's disease and incontinence;emesis, including acute, delayed and anticipatory emesis, for example,induced by chemotherapy, radiation, toxins, pregnancy, vestibulardisorders, surgery, migraine and variations in intercranial pressure;disorders of bladder function such as cystitis and bladder detrusorhyperreflexia; fibrosing and collagen diseases such as scleroderma andeosinophilic fascioliasis; disorders of blood flow caused byvasodilation and vasospastic diseases such as angina, migraine andReynaud's disease; and pain or nociception, for example, thatattributable to or associated with any of the foregoing conditions,especially the transmission of pain in migraine.

The compounds of formula (I) are particularly useful in the treatment ofpain or nociception and/or inflammation and disorders associatedtherewith such as, for example, neuropathy, such as diabetic andchemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis, post operative pain andespecially migraine.

The present invention further provides a compound of formula (I) for usein therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment of physiological disorders associated withan excess of tachykinins, especially substance P.

The present invention also provides a method for the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

For the treatment of certain conditions it may be desirable to employ acompound according to the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of formula (I) may beused in conjunction with a bronchodilator, such as a β₂ -adrenergicreceptor antagonist or tachykinin antagonist which acts at NK-2receptors. The compound of formula (I) and the bronchodilator may beadministered to a patient simultaneously, sequentially or incombination.

The present invention accordingly provides a method for the treatment ofa respiratory disease, such as asthma, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of formula (I) and an effective amount of a bronchodilator.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day. For example, in the treatment of conditionsinvolving the neurotransmission of pain sensations, a suitable dosagelevel is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10mg/kg per day, and especially about 0.005 to 5 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

Compounds of formula (I) wherein A² is NR³, R³ is other than H and thedouble bond is present, may be prepared from intermediates of formula(II): ##STR4## wherein A¹ is O or NR¹ and Q¹, R¹ and R² are as definedfor formula (I), by reaction with an isocyanate of formula R³ NCO whereR³ is as defined for formula (I), other than H, in the presence of abase.

Suitable bases of use in the reaction include organic bases, such as atertiary amine, e.g. triethylamine, and inorganic bases, such as analkali metal hydride, e.g. sodium hydride.

Compounds of formula (I) wherein A² is NH and the double bond is presentmay be prepared by reaction of an intermediate of formula (II) with anisocyanate of formula R²⁰ ₃ SiNCO, where R²⁰ is alkyl, such as methyl,in the presence of a base, as previously described.

Compounds of formula (I) wherein Z is O and the double bond is presentmay be prepared by treatment of a compound of formula (III) ##STR5##wherein Q¹ and R² are as defined for formula (I), and Y represents anactivated carbamate, with a base, such as an alkali metal hydride, e.g.sodium hydride.

Suitably Y may represent an appropriately substituted aryl carbamate,e.g. ##STR6##

The reaction is conveniently effected in a suitable organic solvent,such as, for example, dimethyl formamide.

Compounds of formula (I) wherein the double bond is absent may beprepared from compounds of formula (IV) ##STR7## wherein A¹ is O or NR¹and Q¹, Z, R¹ and R² are as defined for formula (I), by reaction withphosgene or a "phosgene equivalent" such as carbonyl diimidazole, adialkyl carbonate or an alkylchloroformate, preferably with carbonyldiimidazole.

The reaction may be effected under basic conditions. Suitable basesinclude, for example, tertiary amines such as triethylamine.

The reaction is conveniently effected in a suitable organic solvent suchas an ether, e.g. tretrahydrofuran, or a halogenated hydrocarbon, e.g.dichloromethane, suitably at room temperature.

Compounds of formula (I) may also be prepared from other compounds offormula (I). Thus, for example, compounds of formula (I) wherein thedouble bond is absent may in general be prepared from the correspondingcompounds of formula (I) wherein the double bond is present, byreduction. Suitable reduction methods include, for example,hydrogenation in the presence of a catalyst, such as a nobel metalcatalyst, e.g. palladium, which maybe supported, e.g. on carbon.Compounds of formula (I) wherein R¹ and/or R³ is other than H may beprepared from compounds of formula (I) wherein R¹ and/or R³ represent H,by conventional procedures, for example alkylation.

Suitable alkylating agents and procedures will be readily apparent tothose skilled in the art and include, but are not limited to, reactionwith a suitable optionally substituted alkyl halide in the presence of abase, such as an alkali metal hydride, e.g. sodium hydride.

Compounds of formula (II) may be prepared from intermediates of formula(V): ##STR8## wherein A¹ is O or NR¹ and Q¹, R¹ and R² are as definedfor formula (I), by reduction.

Suitable reduction procedures include catalytic hydrogenation. Suitablehydrogenation catalysts include nobel metals, for example, platinum orpalladium, or oxides thereof, which may be supported, for example, oncharcoal.

The reaction is conveniently effected in a suitable organic solvent,such as an ether, e.g. tetrahydrofuran, an alcohol, e.g. ethanol, or anester, e.g. ethyl acetate, suitably at ambient temperature.

Intermediates of formula (V) may be prepared by reaction of an aldehydeof formula R² CHO with a compound of formula (VI): ##STR9## wherein A¹is O or NR¹ and Q¹ and R¹ are as defined for formula (I) and R¹⁶represents a group PR^(x) ₃ or PO(OR^(x))2, wherein R^(x) representsphenyl or C₁₋₁₀ alkyl, in the presence of a base.

Suitable bases include alkali metal hydrides, such as, for example,sodium hydride, and strong organic bases such as, for example,1,8-diazabicylo[5.4.0] undec-7-ene in the presence of anhydrous lithiumchloride.

The reaction is conveniently effected in a suitable organic solvent,such as an ether, e.g. tetrahydrofuran, suitably at ambient temperature.

Compounds of formula (VI) may be prepared from compounds of formula(VII): ##STR10## wherein A¹ is O or NR¹ and Q¹ and R¹ are as defined forformula (I) and R¹⁷ represents an alkoxy or a suitably substituted aminogroup, such as a group NR^(Y) OR^(z), where R^(y) and R^(z) representalkyl, in particular a group NCH₃ (OCH₃), by reaction with a compound offormula CH₃ PO(OR^(x))₂, where R^(x) is an alkyl group, in the presenceof a base.

Suitable reaction procedures will be readily apparent to the skilledperson and examples thereof are described in the accompanying Examples.

Suitable bases of use in the reaction include alkyl lithiums, such asbutyl lithiums.

Compounds of formula (VII) are commercially available or may be preparedusing standard procedures well known to the person skilled in the art.The compounds of formula (VII) where A¹ is NR¹ are amino acidderivatives. Syntheses of amino acids and derivatives thereof are welldocumented and are described, for example, in Chemistry and Biochemistryof the Amino Acids, ed. G. C. Barrett, Chapman and Hall, 1985.

Compounds of formula (III) may be prepared from compounds of formula(II) by reaction with a suitable chloroformate, for example ##STR11## inthe presence of a base, such as a tertiary amine, for example,triethylamine.

Compounds of formula (IV) wherein Z is O may be prepared from compoundsof formula (II) by reduction. Suitable reducing agents include, forexample, hydride reducing agents such as, for example, sodiumborohydride.

Compounds of formula (IV) wherein Z is S may be prepared from thecorresponding compounds of formula (IV) wherein Z is O by treatment withLawesson's reagent or phosphorous pentasulphide in a suitable solvent,e.g. pyridine, at ambient or elevated temperature.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated, suitably by conventional techniques such aspreparative chromatography.

The novel compounds may be prepared in racemic form, or individualenantiomers may be prepared either by enantiospecific synthesis or byresolution. The novel compounds may, for example, be resolved into theircomponent enantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (-)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The novel compounds may also beresolved by formation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

Using the methods described in PCT/GB92/01212 (International PublicationNo. WO 93/01159), pages 30-33, it was found that the compounds of theExamples referred to hereinafter had IC₅₀ at NKIR of less than 500 nM.

The following non-limiting Examples illustrate the preparation ofcompounds according to the invention.

EXAMPLE 11-Methyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one(a) N-Methoxy-N-methyl2-t-butyloxycarbonylamino-3-(3-indolyl)propionamide

N-α-BOC-L-tryptophan (100 g) was dissolved in dimethyl formamide (800ml) and triethylamine (101 g) was added. The reaction was cooled to -30°C. and isobutyl chloroformate (42.5 ml) was added, maintaining theinternal temperature to below -20° C. The reaction was stirred for 15minutes before adding N,O-dimethyl hydroxylamine hydrochloride (64 g)and then diluting the reaction with dichloromethane (1 l), maintainingthe internal temperature below 0° C. The reaction was stirred for 15minutes, poured into ethyl acetate (31) and washed with 10% citric acid(1 l), water (3×1 l), saturated sodium bicarbonate (1 l) and water (1l). The organic phase was dried (MgSO₄), filtered, and evaporated untilcrystallisation ensued. The suspension was diluted with petroleum ether,filtered and dried to yield the title compound; mp 129°-130° C.; ¹ H NMR(360MHz, D₆ DMSO) δ 10.80 (1H, s); 7.51 (1H, d, J=7Hz); 7.33 (1H, d,J=7Hz); 7.16 (1H, s); 7.08-6.97 (3H, m); 4.62-4.58 (1H, m); 3.72 (3H,s); 3.34 (3H, s); 3.02-2.81 (2H, m); 1.31 (9H, s).

(b) 2-t-Butyloxycarbonylamino-1-(3-indolyl)-4-dimethylphosphono-3-butanone

Dimethyl methane phosphonate (205 g) was dissolved in tetrahydrofuran(800 ml), cooled to -70° C.; and then treated with n-butyllithium (1.6Min hexane, 900 ml), maintaining the internal temperature of the reactionat below -55° C. The reaction was stirred for one hour before adding theproduct of part (a) (90 g). The reaction was stirred at -70° C. for 30minutes before quenching with saturated ammonium chloride. The resultingmixture was extracted with ethyl acetate and the organic extract waswashed with water (5×500 ml), dried (MgSO₄) and evaporated. The residuewas purified on silica (eluting with ethyl acetate) to yield the titlecompound as an oil; ¹ H NMR (360MHz, CDCl₃) δ 10.84 (1H, s), 7.56 (1H,d, J=7Hz), 7.33 (1H, d, J=7Hz), 6.98 (1H, t, J=7Hz), 4.34-4.31 (1H, m),3.63 (6H, d, J=11Hz), 3.39 (2H, d, J=22Hz), 3.19-3.11 (1H, m), 2.91-2.84(1H, m); found: C, 55.73, H, 6.34; N, 6.80; C₁₉ H₂₇ N₂ O₆ P requires C,55.60; H, 6.63; N, 6.82%.

(c)5-(3,5-Bis(trifluoromethyl)phenyl)-2-t-butyloxycarbonylamino-1-(3-indolyl)-4-penten-3-one

A solution of the product of part (b) (69.0 g) in acetonitrile (600 ml)was stirred with diisopropylethylamine (43.3 g), and anhydrous lithiumchloride (14.13 g) for 30 minutes before adding3,5-bistrifluoromethylbenzaldehyde (55 g) in acetonitrile (200 ml). Thereaction was stirred for two hours then the solvent was removed and theresidue partitioned between ethyl acetate and water. The organic phasewas washed with 10% citric acid (500 ml), water (500 ml), saturatedsodium bicarbonate (500 ml) and water (500 ml). The solution was dried(MgSO₄), filtered and evaporated. The residue was purified by columnchromatography on silica using ethyl acetate/petroleum ether (1:4) toyield the title compound as a pale yellow solid, mp 137°-138° C.; found:C, 59.23; H, 4.79; N, 5.35; C₂₆ H₂₄ F₆ N₂ O₃ requires C, 59.32; H, 4.60;N 5.32%.

(d)5-(3,5-Bis(trifluoromethyl)phenyl)-2-t-butyloxycarbonylamino-1-(3-indolyl)-3-pentanone

The product of part (c) was heated under reflux with tri-n-butyltinhydride (51.12 g) in toluene for 20 hours. The reaction was cooled andpurified by column chromatography on silica using ethylacetate/petroleum ether (1:4) to yield the title compound as a whitesolid (37.1 g), mp 138°-140° C.: found: C, 59.23; H,4.90; N, 5.28; C₂₆H₂₄ F₆ N₂ O₃ requires C, 59.09, H, 4.96; N, 5.30%.

(e) 2-Amino-5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-3-pentanoneHydrochloride

The product of part (d) was treated with ethereal hydrogen chloride forone hour. The precipitated white solid was filtered and dried, mp84°-86° C.; found: C, 54.40; H, 4.25; N, 6.10; C₂₁ H₁₈ F₆ N₂ O. HClrequires C, 54.26; H, 4.12; N, 6.03%.

(f)1-Methyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one

To a stirred suspension of the compound of part 1(e) (475 mg) indichloromethane (15 ml) was added methyl isocyanate (0.15 ml) andtriethylamine (0.5 ml). After 1.5 hours the reaction was washed withdilute hydrochloric acid, then aqueous sodium bicarbonate, dried (Na₂SO₄) and concentrated. Crystallisation from ethyl acetate/diethyl ethergave the title compound, mp 191° C.; Found: C, 58.07; H, 3.99; N, 8.84.C₂₃ H₁₉ F₆ N₃ O.0.5H₂ O requires C, 57.99; H, 4.23; N, 8.82.

EXAMPLE 2 4-(3,5-Bis(trifluoromethyl)phenethyl)-5-(indol-3-ylmethyl)imidazolin-2-one

Prepared by the method of Example 1(f) using trimethylsilylisocyanateand obtained as white crystals, mp 194°-195° C.; found: C, 57.66; H,3.72; N, 9.16. C₂₂ H₁₇ F₆ N₃ O.0.25H₂ O requires C, 57.71; H, 3.85; N,9.18.

EXAMPLE 3 4-(Indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)oxazolin-2-one (a)2-(4-Nitrophenoxycarbonylamino)-5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-3-pentanone

The compound of Example 1(e) (1 g) in tetrahydrofuran (10 ml) wastreated with bis-(4-nitrophenyl)carbonate (0.66 g) and triethylamine(0.3 ml). After stirring for 24 hours the reaction was diluted withethyl acetate, washed with water, dried (Na₂ SO₄) and concentrated.Crystallisation from ethyl acetate-petroleum ether gave the titlecompound as a white solid.

(b) 4-(Indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)oxazolin-2-one

A solution of the product of Example 3(a) (300 mg) in dimethylformamide(5 ml) was treated with sodium hydride (20 mg of a 60% dispersion inoil) for 16 hours. The reaction was diluted with ethyl acetate, washedwith water, dried (NaSO₄) and concentrated. The residue was purified bychromatography on silica gel eluting with ethyl acetate-petroleum etherto give the title compound which was recrystallised from ethylacetate-petroleum ether, mp 178°-180° C.; found: C, 58.01; H, 3.75; N,6.11. C₂₂ H₁₆ F₆ N₂ O₂ requires C, 58.16; H, 3.55; N, 6.16.

EXAMPLE 4 4-(Indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)oxazolidin-2-one (a)5-(3,5-Bis(trifluoromethyl)phenyl)-2-t-butoxycarbonylamino-1-(1-t-butoxycarbonylindol-3-yl)-3-pentanone

The product of Example 1(d) (6.7 g) in dichloromethane (200 ml) wastreated with di-tertbutyl dicarbonate (2.75 g) andN,N-dimethylaminopyridine (1.5 g) for 2 hours. The reaction mixture waswashed with aqueous citric acid, sodium bicarbonate solution and waterthen dried (Na₂ SO₄) and concentrated to give an oil which was purifiedby chromatography on silica gel. A sample of the product thus obtained(2 g) was dissolved in methanol and treated with sodium borohydride (120mg) for 1 hour. The solvent was evaporated and the residue partitionedbetween ethyl acetate and water. The organic solution was separated,dried and concentrated to give a residue which was purified bychromatography on silica to give the title compound as two separatediastereomers, isomer A and isomer B.

(b) 4-(Indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)oxazolidin-2-one

The compound of Example 4(a), isomer A (70 mg), was dissolved inethereal hydrogen chloride for 1 hour. The mixture was concentrated andthe residue dissolved in dichloromethane (5 ml) to which was addedtriethylamine (0.5 ml) and carbonyl diimidazole (100 mg). After stirringfor 1 hour the reaction was diluted with ethyl acetate, washed withdilute hydrochloric acid then sodium bicarbonate solution, dried andconcentrated. Chromatography on silica gel eluting with ethylacetate-petroleum ether (1:3) gave the title compound, isomer A, mp196°-198° C.; found: C, 55.80; H, 4.02; N, 5.96. C₂₂ H₂₀ F₆ N₂ O₃requires C, 55.70; H, 4.25; N, 5.91.

In a similar manner the compound of Example 4(a), isomer B, gave thetitle compound, isomer B.

EXAMPLE 5 1-Ethyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one

To a stirred suspension of the compound of Example 1(e) (468 mg) indichloromethane (15 ml) was added ethyl isocyanate (0.5 ml) andtriethylamine (1 ml). After 1 hour the solution was washed with dilutehydrochloric acid, aqueous sodium bicarbonate, dried (Na₂ SO₄) andconcentrated. The residue was dissolved in methanol 5 ml and treatedwith sodium methoxide (0.4 g) for 1.5 hours after which time thesolution was diluted with dichloromethane, washed with water, dried andconcentrated. Crystallisation from diethyl ether gave the titlecompound, mp 228°-230° C.; found: C, 59.15; H, 4.42; N, 8.55. C₂₄ H₂₁ F₆N₃ O.0.25H₂ O requires C, 59.32; H, 4.46; N, 8.65.

EXAMPLE 61-(4-Pyridylmethyl)-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one

a)5-(3,5-Bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(4-pyridylmethylureido)-3-pentanoneHydrochloride

The compound of Example 1(e) (400 mg) in tetrahydrofuran (10 ml) wastreated with triethylamine (0.12 ml) and 4-nitrophenylchloroformate (174mg) for 1 hour. The solvent was removed in vacuo and the residuepartitioned between ethyl acetate and water. The organic solution wasdried (Na₂ SO₄) and concentrated to give a solid which was dissolved intetrahydrofuran (15 ml). 4-Aminomethylpyridine (0.085 ml) was added andthe solution stirred for 16 hours then concentrated in vacuo. Theresidue was partitioned between ethyl acetate and potassium carbonatesolution. The organic solution was dried (Na₂ SO₄), concentrated and theresidue treated with ethereal hydrogen chloride to give the titlecompound, mp 171°-174° C.; found: C, 53.94; H, 4.31; N, 8.87%. C₂₇ H₂₅F₆ N₄ O₂.HCl.1.5H₂ O requires C, 53.72; H, 4.50; N, 8.95%.

b)1-(4-Pyridylmethyl)-4-(indol-3-ylmethyl)-5-(3.5-bis(trifluoromethyl)phenethyl)imidazolin-2-one

The compound of part 7(a) (0.1 g) in methanol (5 ml) was treated withsodium methoxide (225 mg) for 16 hours, then diluted with ethyl acetate,washed with water, dried and concentrated. Crystallisation of theresidue from ethyl acetate-petroleum ether gave the title compound, mp222°-224° C.; found: C, 61.61; H, 4.31; N, 10.07. C₂₈ H₂₂ F₆ N₄ Orequires C, 61.76; H, 4.07; N, 10.29.

EXAMPLE 71-Dimethylaminoethyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one

Prepared by the method of Example 6 using 2-N,N-dimethylaminoethylamine.Mp 189°-191° C.; found: C, 58.73; H, 4.82; N, 10.40. C₂₆ H₂₆ F₆ N₄O.0.3H₂ O requires C, 58.93; H, 5.05; N, 10.52.

EXAMPLE 81-Methyl-3-methyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one

The compound of Example 1 (0.5 g) in tetrahydrofuran (5 ml) was treatedwith sodium hydride (43 mg of a 60% dispersion in oil) under a nitrogenatmosphere with stirring. After 5 minutes methyl iodide (0.28 g) wasadded and stirring continued for 2 hours. The reaction was diluted withethyl acetate, washed with water, dried and concentrated. The residuewas purified by chromatography on silica gel eluting with ethylacetate-petroleum ether and crystallised from ethyl acetate-petroleumether to give the title compound, mp 202°-205° C.; found: C, 59.88; H,4.23; N, 8.42. C₂₄ H₂₁ F₆ N₃ O requires C, 59.88; H, 4.40; N, 8.73.

EXAMPLE 91-Dimethylaminopropyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one

Prepared by the method of Example 6 using3-N,N-dimethylaminopropylamine. Mp. 209°-211° C.; found: C, 60.15; H,5.30; N, 10.28. C₂₇ H₂₈ F₆ N₄ O requires C, 60.22; H, 5.24; H, 10.40.

EXAMPLE 101-(4-Piperidinyl)-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one

N-^(t) Butoxycarbonylisonipecotic acid (458 mg) in dichloromethane (10ml) was treated with triethylamine (0.28 ml) and diphenylphosphorylazide (0.43 ml) for 16 hours. The solvent was removed under reducedpressure and the residue redissolved in dichloromethane (15 ml) to whichwas added triethylamine (0.2 ml) and the compound of Example 1(e). Afterstirring for 6 hours the solvent was evaporated and the residuepartitioned between water and ethyl acetate. The ethyl acetate solutionwas separated, dried (Na₂ SO₄) and concentrated to give a residue whichwas purified by chromatography on silica gel eluting with ethylacetate-petroleum ether (1:1). The resulting oil was dissolved inethereal hydrogen chloride for 2 hours. The solution was washed withsodium bicarbonate solution, dried (Na₂ SO₄) and evaporated to give thetitle compound, mp 190° C. (decomp.); found: C, 57.71; H, 4.78; N, 9.67.C₂₇ H₂₆ F₆ N₄ O. 1.5H₂ O requires C, 57.55; H, 5.18; N, 9.94.

EXAMPLE 111-(2-(N-Morpholinyl)ethyl)-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one

Prepared by the method of Example 6 using N-(aminoethyl) morpholine. Mp207° C.; found: C, 59.52; H, 5.13; N, 9.60. C₂₈ H₂₈ F₆ N₄ O₂ requires C,59.36; H, 4.98; N, 9.89.

EXAMPLE 121-(4-Piperidinylmethyl)-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-oneHydrochloride

The compound of Example 1(e) was treated with 4-nitrophenylchloroformateand N-Boc-4-aminomethylpiperidine (Synthetic Communications (1992), 22,2357) by the method of Example 6. After the reaction had stirred for 16hours dichloromethane was added and the solution washed with water,dried and concentrated. The residue was purified by chromatography onsilica gel eluting with ethyl acetate-petroleum ether to give a solidwhich was dissolved in ethereal hydrogen chloride for 16 hours. Thesolvent was removed in vacuo and the residue crystallised frompropan-2-ol/di-isopropyl ether to give the title compound, mp 250° C.(decomp.); found: C, 57.28; H, 4.63; N, 9.34. C₂₈ H₂₈ F₆ N₄ O.HClrequires C, 57.29; H, 4.98; N, 9.54.

EXAMPLE 134-(3,5-Bis(trifluoromethyl)phenethyl)-5-(indol-3-ylmethyl)-3-methyloxazolin-2-one(a)N-Methoxy-N-methyl-2-t-butyldimethylsilyloxy-3-(3-indolyl)propionamide

Indole lactic acid (5.0 g) was suspended in dichloromethane (100 ml) andtreated with triethylamine (6.8 ml) and t-butyldimethylsilyl triflate(5.7 ml) for 24 hours. iso-Butyl chloroformate (3.1 ml) was addedfollowed by N,O-dimethylhydroxylamine (2.4 g) and triethylamine (3.4ml). The solution was stirred for 24 hours then washed with water, dried(Na₂ SO₄) and concentrated. The residue was purified by chromatographyon silica gel eluting with ethyl acetate-petroleum ether to give thetitle compound as a white solid.

(b)5-(3,5-Bis(trifluoromethyl)phenyl)-2-t-butyldimethylsilyloxy-1-(3-indolyl)-4-penten-3-one

Prepared from the compound of Example 13(a) by the methods of Examples1(b) and 1(c).

(c)5-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxy-1-(3-indolyl)-3-pentanone

The compound of Example 13(b) in ethyl acetate was shaken under anatmosphere of hydrogen gas at 50 psi over 10% Pd--C for 24 hours. Themixture was filtered, concentrated and dissolved in tetrahydrofurancontaining tetrabutylammonium fluoride for 3 hours. The solution wasdiluted with water and extracted with diethyl ether which was then driedand concentrated to give a residue which was purified on silica geleluting with ethyl acetate-petroleum ether (2:3). Crystallisation fromdiethyl ether-petroleum ether gave the title compound as a white solid.

(d)4-(3,5-Bis(trifluoromethyl)phenethyl)-5-(indol-3-ylmethyl)-3-methyloxazolin-2-one

The compound of Example 13(c) (0.15 g) was dissolved in methylisocyanate (1 ml). After 6 hours the solution was concentrated in vacuoand the residue dissolved in methanol (2 ml) containing sodium methoxidefor 30 minutes. The solution was diluted with diethyl ether and washedwith 5N hydrochloric acid, dried and concentrated. The residue waspurified on silica gel eluting with ethyl acetate-hexane (2:3) to givethe title compound as a white solid, mp 109°-110 ° C.; found: C, 59.22;H, 3.86; N, 5.70. C₂₃ H₁₈ F₆ N₂ O₂ requires C, 58.98; H, 3.87; N, 5.98.

The following examples illustrate pharmaceutical compositions accordingto the invention.

EXAMPLE 14A Tablets Containing 1-25 mg of Compound

    ______________________________________                                                       Amount mg                                                      ______________________________________                                        Compound of formula (I)                                                                        1.0       2.0    25.0                                        Microcrystalline cellulose                                                                     20.0      20.0   20.0                                        Modified food corn starch                                                                      20.0      20.0   20.0                                        Lactose          58.5      57.5   34.5                                        Magnesium Stearate                                                                             0.5       0.5    0.5                                         ______________________________________                                    

EXAMPLE 14B Tablets Containing 26-100 mg of Compound

    ______________________________________                                                       Amount mg                                                      ______________________________________                                        Compound of formula (I)                                                                        26.0      50.0   100.0                                       Microcrystalline cellulose                                                                     80.0      80.0   80.0                                        Modified food corn starch                                                                      80.0      80.0   80.0                                        Lactose          213.5     189.5  139.5                                       Magnesium Stearate                                                                             0.5       0.5    0.5                                         ______________________________________                                    

The compound of formula (I), cellulose, lactose and a portion of thecorn starch are mixed and granulated with 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0mg, 50.0 mg and 100 mg of the active compound per tablet.

EXAMPLE 15 Parenteral Infection

    ______________________________________                                                            Amount mg                                                 ______________________________________                                        Compound of formula (I)                                                                             1 to 100 mg                                             Citric Acid Monohydrate                                                                             0.75     mg                                             Sodium Phosphate      4.5      mg                                             Sodium Chloride       9        mg                                             Water for Injections  to 1     ml                                             ______________________________________                                    

The sodium phosphate, citric acid monohydrate and sodium chloride aredissolved in a portion of the water. The compound of formula (I) isdissolved or suspended in the solution and made up to volume.

EXAMPLE 16 Topical Formulation

    ______________________________________                                                             Amount mg                                                ______________________________________                                        Compound of formula (I)                                                                              1-10    g                                              Emulsifying Wax        30      g                                              Liquid paraffin        20      g                                              White Soft Paraffin    to 100  g                                              ______________________________________                                    

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. Thecompound of formula (I) is added and stirring continued until dispersed.The mixture is then cooled until solid.

I claim:
 1. A compound of formula (I), or a salt or prodrug thereof:##STR12## wherein Q¹ represents optionally substituted indolyl,optionally substituted benzthiophenyl, or optionally substitutedbenzofuranyl;the dotted line represents an optional covalent bond; oneof A¹ and A² represents NR¹ and the other is NR³ ; R¹ and R³ eachindependently represent H; C₁₋₆ alkyl optionally substituted by hydroxy,cyano, COR^(c), CO₂ R^(c), CONR^(c) R^(d), or NR^(c) R^(d) (where R^(c)and R^(d) each independently represent H, C₁₋₆ alkyl or C₀₋₄ alkylphenyloptionally substituted in the phenyl ring by one or more of C₁₋₆ alkyl,C₁₋₆ alkoxy, halo or trifluoromethylmethyl); phenyl (C₁₋₄ alkyl)(optionally substituted in the phenyl ring by one or more of C₁₋₆ alkyl,C₁₋₆ alkoxy, halo and trifluoromethyl); COR^(c) ; CO₂ R^(c) ; CONR^(c)R^(d) ; COC₁₋₄ alkylNR^(c) R^(d) ; CONR^(c) COOR^(d) ; SO₂ R^(c), whereR^(c) and R^(d) are as above defined; WR⁶ or CO--Y--W--R⁶ where R⁶ is anoptionally substituted aromatic or non-aromatic azacyclic or azabicyclicgroup, Y is a bond, O, S or NR^(y), where R^(y) is H or C₁₋₆ alkyl, andW represents a bond or a saturated or unsaturated hydrocarbon chain of1, 2, 3, 4, 5 or 6 carbon atoms; R² represents phenyl optionallysubstituted by 1, 2, or 3 groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl,OR^(a), SR^(a), SOR^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b),CO₂ R^(a) or CONR^(a) R^(b), where R^(a) and R^(b) independentlyrepresent H, C₁₋₆ alkyl, phenyl or trifluoromethyl.
 2. A compound asclaimed in claim 1 wherein R¹ and R³ each independently represent H;C₁₋₆ alkyl optionally substituted by hydroxy, cyano, COR^(c), CO₂ R^(c),CONR^(c) R^(d), or NR^(c) R^(d) ; phenyl(C₁₋₄ alkyl) (optionallysubstituted in the phenyl ring by one or more of C₁₋₆ alkyl, C₁₋₆alkoxy, halo and trifluoromethyl); COR^(c) ; CO₂ R^(c) ; CONR^(c) R^(d); COC₁₋₄ alkylNR^(c) R^(d) ; CONR^(c) COOR^(d) ; SO₂ R^(c) ; (CH₂)_(q)R⁶ or CO(CH₂)_(q) R⁶ where q is 0, 1, 2, 3, 4, 5 or
 6. 3. A compound offormula (I) or a pharmaceutically acceptable salt thereof as claimed inclaim 1 wherein the double bond is present.
 4. A compound as claimed inclaim 1 wherein R³ is H or C₁₋₃ alkyl.
 5. A compound as claimed in claim1 wherein R³ reprsents C₁₋₆ alkyl substituted by NR^(c) R^(d) orY--W--R⁶.
 6. A compound as claimed in claim 1 wherein R² is phenylsubstituted by one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl.
 7. A compound as claimed in claim 1 selectedfrom:1-methyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one;4-(3,5-bis(trifluoromethyl)phenethyl)-5-(indol-3-ylmethyl)imidazolin-2-one;1-ethyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one;1-(4-pyridylmethyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one;1-dimethylaminoethyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one;1-methyl-3-methyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one;1-dimethylaminopropyl-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one;1-(4-piperidinyl)-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one;1-(2-(N-morpholinyl)ethyl)-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-one;1-(4-piperidinylmethyl)-4-(indol-3-ylmethyl)-5-(3,5-bis(trifluoromethyl)phenethyl)imidazolin-2-onehydrochloride;and their pharmaceutically acceptable salts and prodrugsthereof.
 8. A pharmaceutical composition comprising a compound asclaimed in claim 1 in association with a pharmaceutically acceptablecarrier.
 9. A method for the treatment of a physiological disorderassociated with an excess of tachykinins, which method comprisesadministration to a patient in need thereof of a tachykinin-reducingamount of a compound according to claim
 1. 10. A method according toclaim 9 for the treatment of pain or inflammation.
 11. A methodaccording to claim 9 for the treatment of migraine.
 12. A methodaccording to claim 9 for the treatment of arthritis.